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Mosaicism of Activating FGFR3 Mutations in Human Skin Causes Epidermal Nevi

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Mosaicism of Activating FGFR3 Mutations in Human Skin Causes Epidermal Nevi Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi Christian Hafner, … , Ellen C. Zwarthoff, Arndt Hartmann J Clin Invest. 2006;116(8):2201-2207. https://doi.org/10.1172/JCI28163. Research Article Dermatology Epidermal nevi are common congenital skin lesions with an incidence of 1 in 1,000 people; however, their genetic basis remains elusive. Germline mutations of the FGF receptor 3 (FGFR3) cause autosomal dominant skeletal disorders such as achondroplasia and thanatophoric dysplasia, which can be associated with acanthosis nigricans of the skin. Acanthosis nigricans and common epidermal nevi of the nonorganoid, nonepidermolytic type share some clinical and histological features. We used a SNaPshot multiplex assay to screen 39 epidermal nevi of this type of 33 patients for 11 activating FGFR3 point mutations. In addition, exon 19 of FGFR3 was directly sequenced. We identified activating FGFR3 mutations, almost exclusively at codon 248 (R248C), in 11 of 33 (33%) patients with nonorganoid, nonepidermolytic epidermal nevi. In 4 of these cases, samples from adjacent histologically normal skin could be analyzed, and FGFR3 mutations were found to be absent. Our results suggest that a large proportion of epidermal nevi are caused by a mosaicism of activating FGFR3 mutations in the human epidermis, secondary to a postzygotic mutation in early embryonic development. The R248C mutation appears to be a hot spot for FGFR3 mutations in epidermal nevi. Find the latest version: https://jci.me/28163/pdf Research article Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi Christian Hafner,1 Johanna M.M. van Oers,2 Thomas Vogt,1 Michael Landthaler,1 Robert Stoehr,3 Hagen Blaszyk,4 Ferdinand Hofstaedter,5 Ellen C. Zwarthoff,2 and Arndt Hartmann5 1Department of Dermatology, University of Regensburg, Regensburg, Germany. 2Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands. 3Department of Urology, University of Regensburg, Regensburg, Germany. 4Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont, USA. 5Institute of Pathology, University of Regensburg, Regensburg, Germany. Epidermal nevi are common congenital skin lesions with an incidence of 1 in 1,000 people; however, their genetic basis remains elusive. Germline mutations of the FGF receptor 3 (FGFR3) cause autosomal dominant skeletal disorders such as achondroplasia and thanatophoric dysplasia, which can be associated with acan- thosis nigricans of the skin. Acanthosis nigricans and common epidermal nevi of the nonorganoid, nonepi- dermolytic type share some clinical and histological features. We used a SNaPshot multiplex assay to screen 39 epidermal nevi of this type of 33 patients for 11 activating FGFR3 point mutations. In addition, exon 19 of FGFR3 was directly sequenced. We identified activating FGFR3 mutations, almost exclusively at codon 248 (R248C), in 11 of 33 (33%) patients with nonorganoid, nonepidermolytic epidermal nevi. In 4 of these cases, samples from adjacent histologically normal skin could be analyzed, and FGFR3 mutations were found to be absent. Our results suggest that a large proportion of epidermal nevi are caused by a mosaicism of activating FGFR3 mutations in the human epidermis, secondary to a postzygotic mutation in early embryonic develop- ment. The R248C mutation appears to be a hot spot for FGFR3 mutations in epidermal nevi. Introduction domains (Figure 2). Alternative splicing of the second half of the Epidermal nevi show a prevalence of about 1 in 1,000 people and IgIII-like domain (exon 8 versus exon 9) results in the isoforms can be divided into either nonorganoid (keratinocytic) types or IIIb and IIIc. The isoforms show different ligand specificity and organoid types characterized by hyperplasia of adnexal structures tissue expression. FGFR3 IIIb is mainly expressed in epithelial cells such as sebaceous glands, sweat glands, and hair follicles. Epider- while FGFR3 IIIc is predominantly found in mesenchymal cells (5). mal nevi of the common, nonorganoid and nonepidermolytic type This paper assigns all codon numbers to the open reading frame of are benign skin lesions and may vary in their extent from a single the FGFR3 IIIb isoform. More than 20 FGFs are known as ligands (usually linear) lesion to widespread and systematized involvement now (4). The interaction of the ligand with the receptor requires (Figure 1). They may be present at birth or develop early during the presence of sulfated glycosaminoglycans such as heparin and childhood as localized epidermal thickening with hyperpigmenta- leads to the dimerization of the receptor with consecutive phos- tion, frequently following the lines of Blaschko. This suggests that phorylation of intracellular tyrosine residues in the kinase domain epidermal nevi may be due to mosaicism resulting from postzygot- and activation of intracellular signaling pathways. The autophos- ic mutations in keratinocytes. Mutations of keratins 1 and 10 were phorylation sites of FGFR3 represent potential binding sites for shown to be responsible for a rare subgroup of epidermal nevi, signaling proteins, for example, with phosphotyrosine binding the linear epidermolytic hyperkeratosis (1, 2). Another variant of (PTB) and Src homology 2 (SH2) domains. Activation of the cyto- epidermal nevi, the congenital hemidysplasia with ichthyosiform plasmic region causes phosphorylation of Shp2, PLCg, ERK1/2, nevus and limb defects (CHILD) nevus, is caused by NADPH ste- and STAT3 and also PI3K activation (4). FGFRs can also be acti- roid dehydrogenase-like protein (NSDHL) mutations (Xq28) and vated by interaction with EphA4, another receptor tyrosine kinase, represents a functional X chromosomal mosaicism (3). However, which demonstrates the complexity of FGFR signaling (6). the genetic basis of the much more common nonorganoid, non- Activating germline mutations of the FGFR3 gene result in dwarf- epidermolytic keratinocytic epidermal nevi remains elusive. ism, severe skeletal dysplasia, and craniosynostosis syndromes such The FGF receptor (FGFR) family comprises 4 major trans- as achondroplasia (ACH), hypochondroplasia (HCH), thanato- membrane receptor tyrosine kinases (FGFR1–4) and is involved phoric dysplasia (TD), Crouzon syndrome (CS), Muenke syndrome in embryogenesis, angiogenesis, and tissue homeostasis (4). The (MS), and SADDAN (severe achondroplasia with developmental FGFR3 gene contains 19 exons encoding an extracellular region delay and acanthosis nigricans) syndrome (7–10). These activating for ligand binding composed of 3 Ig-like domains, a hydropho- mutations result in negative chondrocytic growth regulation of bic transmembrane domain and 2 cytoplasmic tyrosine kinase the epiphyseal plates of long bones, causing dwarfism (11). Identi- cal mutations are found in different cancer entities and probably provide proliferative signals (4). FGFR3 signaling in mutated cells Nonstandard abbreviations used: ACH, achondroplasia; CS, Crouzon syndrome; is poorly understood, but previous studies provide some insights. FGFR3, fibroblast growth factor receptor 3; HCH, hypochondroplasia; SADDAN, severe achondroplasia with developmental delay and acanthosis nigricans; All known missense mutations causing TD I create an unpaired TD, thanatophoric dysplasia. cysteine residue (12–14), such as the R248C and S249C mutations. Conflict of interest: The authors have declared that no conflict of interest exists. These mutations are localized in the extracellular domain at the Citation for this article: J. Clin. Invest. 116:2201–2207 (2006). doi:10.1172/JCI28163. linker region between the Ig-like domains II and III while other The Journal of Clinical Investigation http://www.jci.org Volume 116 Number 8 August 2006 2201 research article Figure 1 Patient 29 displayed a systematized epidermal nevus of the common soft type with involvement of the face (bilateral), the right scapular region, the right arm, the right hip, and the right thigh. Abnormalities of the skel- etal or nervous system were not present. A biopsy was taken from the epidermal nevus of the right forearm. This epidermal nevus revealed an R248C FGFR3 gene mutation. DNA isolated from the blood of this patient revealed WT status at codon 248, excluding a germline mutation. to the formation of hydrogen bonds between 2 FGFRs, resulting in constitutive receptor activation (20). The A393E mutation in CS also affects the transmembrane domain and results in FGFR3 dimer stabilization, measured by the change in the free energy of the dimerization, thus largely increasing the fraction of dimers (21). A third class of mutations affect the tyrosine kinase domain, such as the K652E mutation in TD II or the N542K mutation in HCH (11). These mutations likely cause conformational changes in the activation loop that activate the receptor tyrosine kinase activity and downstream ERK1/2 (22). Other studies suggest that FGFR3 mutations may delay the downregulation and ligand-medi- ated internalization of the receptor (23). The phosphorylated immature form of the mutant receptor accumulates in the endo- plasmic reticulum and fails to be degraded (24). The different degree of receptor activation seems to correlate with the severity of the phenotype. Stronger activation of the receptor by ligand-inde- pendent dimerization via disulfide bonds in TD patients deter- mines the more severe phenotype compared with other skeletal dysplasia syndromes such as ACH and HCH (15, 25). Somatic activating FGFR3
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